Mild traumatic brain injury (mTBI) caused by blast effects of explosive devices is the signature injury of service members deployed to combat operations in Iraq and Afghanistan. Resultant persistent postconcussive symptoms (PCS), such as impairment of memory and concentration, irritability, mood instability, and sleep disturbances, frequently have disabling personal, professional and domestic consequences. In addition to these immediate consequences, repetitive mTBI may initiate processes leading to neurodegeneration and dementia. This application is a resubmission of a proposal to continue a currently funded VA RR&D Merit Review: B77421, Mild TBI and Biomarkers of Neurodegeneration. In the current funding period, we have made substantial progress in 1) identifying objective structural and functional neuroimaging biomarkers that characterize the clinical phenotype of blast-induced mTBI and distinguish mTBI from combat trauma posttraumatic stress disorder (PTSD), 2) identifying objective impairment of cognitive function in mTBI Veterans using our refined neuropsychological assessment battery, 3) identifying a potential mTBI-specific cerebrospinal fluid (CSF) biomarker, and 4) identifying unanticipated CSF neurodegenerative and neuroinflammatory biomarkers of deployment independent of presence or absence of mTBI. We have integrated neuroimaging, cognitive, and biomarker findings into a consistent model of regional brain dysfunction in repetitive blast mTBI. Goals of this continuation proposal are to determine whether cognitive performance is associated with CSF biomarkers of and/or genetic risk factors for neurodegenerative dementia, and to determine whether neuroimaging and CSF biomarker abnormalities are transient, static, or progressive. We also propose three new clinical assessments: in-theater sleep history, sleep/activity monitoring via Actigraphy, and balance/vestibular function testing; and two additional neuroimaging analyses: white matter tractography and susceptibility weighted imaging (SWI) for detection of microhemorrhages. Specific Objective 1: To continue characterizing longitudinally the clinical (neurocognitive, neurologic, behavioral) and structural/functional neuroimaging characteristics of disrupted cerebellar-thalamic- frontoparietal cortical function in OIF/OEF/OND Veterans with repetitive blast trauma mTBI. Specific Objective 2: To determine if OEF/OIF/OND Veterans with repetitive mTBI exhibit CSF biomarker changes associated with the onset and progression of neurodegenerative dementing disorders, such as chronic traumatic encephalopathy (CTE) and Alzheimer's disease (AD). Specific Objective 3: To determine the effects of genetic risk factors for neurodegeneration (apolipoprotein E [APOE] polymorphisms and microtubule associated protein tau [MAPT] subhaplotypes) on both clinical characteristics and CSF biomarkers in OEF/OIF/OND Veterans with repetitive mTBI. This proposal addresses the RR&D priority areas of Validation and Refinement of Diagnostic Imaging Technology and Innovative Approaches to Late or Long-Term Consequences of TBI. VHA faces a huge burden of providing primary medical, rehabilitative, mental health and long term care to this vulnerable population. Identification of objective neuroimaging and CSF biomarkers of mTBI and clarification of the long- term risks of neurodegenerative dementias in mTBI will: improve diagnosis of mTBI and ability to monitor response to potential treatments; provide targets for improving Veterans' health care; and allow appropriate allocation of limited VHA resources. Successful completion of the proposed research has a high likelihood of yielding both short-term and long-term clinical impacts. The project will yield tools for objective biomarker diagnosis of mTBI and form the evidence base for rational design of clinical trials to treat current symptoms of mTBI and to prevent progression to neurodegenerative dementing disorders.